Chapter 105. Cutaneous Manifestations of Drug Abuse

Drug abuse and addiction can be suspected or diagnosed on the basis of mucosal and cutaneous findings. The administration of drugs may cause cutaneous stigmata and eruptions predominantly through local or systemic, toxic or hypersensitivity-induced effects as a result of the drug itself, adulterants, infectious agents, or the mode of drug delivery.

Illicit drug use is a maladaptive pattern involving self-administration of prescribed or recreational drugs. Chipping is a lay term used to describe a pattern of drug use in which the user is not physically dependent, but rather sustains “controlled use” of a drug. A certain percentage of users will progress to drug dependence, a physical and/or psychological need for the effects of a chemical in order to avoid withdrawal symptoms associated with abstinence (Box 105-1). Drug dependence often leads to drug abuse, an intense desire to recurrently obtain increasing amounts of one or more chemical substances to the exclusion of all other activities, resulting in clinically significant physical, emotional or social distress (Box 105-2). Tolerance defines a physiologic state in which progressive increases in the dose of a drug are needed to achieve the effects previously experienced at smaller doses. Some drugs chiefly induce physical dependence, while cause predominantly psychological dependence.1

The National Institute of Drug Abuse (NIDA) (http://www.drugabuse.gov/)2 considers the following agents to be drugs of abuse in the United States:

• Alcohol
• Club drugs
• Cocaine
• Heroin
• Inhalants
• Lysergic acid diethylamide (LSD)
• Marijuana
• 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)
• Methamphetamine
• Phencyclidine (PCP)
• Prescription medications
• Steroids (anabolic)
• Tobacco

Betel is widely used in South Asia, Southeast Asia and the South Pacific.

In 2004, the United Nations’ World Drug Report estimated that between 3% and 5% of the global population used illicit drugs.3 In 2008, the National Survey on Drug Use and Health in the United States estimated that:

• 20.1 million Americans aged 12 or older (8% of that population) were currently using illicit drugs including marijuana/hashish, cocaine, crack, heroin, hallucinogens, inhalants or prescription-type psychotherapeutics.
• Marijuana was the most commonly used illicit drug (15.2 million past month users).
• The most commonly injected drugs were heroin and cocaine.
• Almost 2 million current cocaine users, comprising 0.7% of the population, were estimated.4
• The actual number of individuals who use heroin is difficult to determine because there has been a growing tendency to sniff, snort or smoke rather than to inject heroin intravenously or subcutaneously.
• An estimated 70.9 million Americans (28.4%) aged 12 or older were current users of tobacco in any form.
• Of Americans aged 12 and older, 51.6% had consumed alcohol at least once in the 30 days prior to being surveyed; 23.3% reported drinking heavily (>5 drinks on >5 occasions).

The drugs most commonly associated with emergency department visits in 2001 included cocaine, marijuana, benzodiazepines and heroin, in that order (Fig. 105-1).

Studies in concordant twins have shown a strong influence of genetic inheritance on the susceptibility to drug use.5 The potential of a drug to cause addiction varies. The processes by which genes regulate physical reactions to addictive drugs have not been clearly elucidated. Repeated exposure to cocaine causes a change at the level of gene expression that leads to altered levels of the specific brain protein called cyclin-dependent kinase-5. This protein regulates the action of dopamine, which potentiates the euphoric effects of cocaine and other drugs.6 Narcotics disable the neurons that normally inhibit the release of dopamine while amphetamines and cocaine increase dopamine signaling, either by directly stimulating its release, or by blocking its absorption. Environmental factors such as history of sexual abuse during childhood, severe family dysfunction with drug abusing, detached or mentally ill parents, poor social skills, and drug-using peers are also clearly important.

The mechanisms of addiction, tolerance and dependence are complex. Addictive drugs flood the synapses of the mesolimbic system, especially the nucleus accumbens, with excessive amounts of dopamine, augmenting the hedonic tone and producing a euphoric state. The subsequent pleasurable reactions of the frontal cortex, amygdala, and hippocampus are exaggerated. The association of drug use and euphoria in these brain areas is reinforced with each exposure until the user no longer controls behavior, at which point addiction has resulted.7 Chronic users have sustained activation of the cAMP response element-binding (CREB) protein, a trigger for the production of dynorphin and other proteins that shut off dopamine release, preventing the individual from finding pleasure in usually enjoyable activities and requiring subsequent fixes with higher doses of drug to overcome the effects of tolerance. Addictive drugs also inhibit or excite neuronal activity in various areas of the nervous system. To compensate for these alterations, neuroadaptation develops with either formation of new neuroreceptor sites or diminished synthesis and sensitivity of neurotransmitters and neuroreceptor sites. Discontinuation of the drug reverses the neuroadaptation process and results in an exaggerated neural response that produces withdrawal symptoms.

Alcohol

Ethyl alcohol, or ethanol, is the intoxicating ingredient found in alcoholic beverages. It is a central nervous system depressant that impairs brain function and motor skills and is rapidly absorbed from the stomach and small intestine into the bloodstream. Heavy use can increase the risk of liver disease, stroke and certain cancers.

Direct liver toxicity of alcohol can cause hepatomegaly, jaundice, shrunken liver in the setting of cirrhosis, and hypoalbuminemia leading to Muehrcke lines and Terry nails (see Chapter 89). Hyperestrogenemia can lead to gynecomastia, palmar erythema, spider angiomata, and testicular atrophy. Portal hypertension secondary to alcohol-induced liver cirrhosis can lead to an enlarged spleen, ascites, variceal bleeding, hemorrhoidal bleeding and caput medusae. Dupuytren contractures due to fibroblastic proliferation and disorderly collagen deposition may be seen in 66% of alcohol abusers. Asterixis and confusion are seen in patients with hepatic encephalopathy. Alcohol withdrawal delirium, also known as delirium tremens, is characterized by tachycardia, hypertension, body temperature elevation and delirium. Ataxia, confusion and lateral gaze palsy are indications of Wernicke encephalopathy. Wernicke encephalopathy followed by anterograde and retrograde amnesia along with confabulation characterize Korsakoff syndrome.

Club Drugs

Club drugs include γ-hydroxybutyric acid (GHB, date rape drug), flunitrazepam (Rohypnol®, roofies), ketamine, MDMA, and LSD (Table 105-1). These drugs tend to be used by teenagers and young adults in social settings. In 2008, NIDA showed that among 12th graders, 1.3% had abused flunitrazepam, 1.2% had abused GHB and 1.5% had abused ketamine at least once in the year prior to their being surveyed.8 GHB is sedating and can cause coma and seizures. It is being used increasingly by bodybuilders, who believe that it helps to metabolize fat and build muscle. Flunitrazepam is also sedating and can incapacitate users and cause amnesia; when combined with alcohol, this drug can be lethal. Ketamine distorts perception and produces feelings of detachment from the environment and self.

Cocaine

Cocaine (benzoylmethylecgonine) is an alkaloid extracted from the leaves of the coca plant Erythroxylon coca.9–15 It is a powerful sympathomimetic, vasoconstrictor, local anesthetic, and stimulant. Cocaine hydrochloride is a powder that can be can be nasally inhaled or injected intravenously or subcutaneously, also known as “skin popping” (Fig. 105-2). Crack cocaine or “crack,” the freebase rock crystal form of cocaine hydrochloride, is smoked (Table 105-1). Freebase refers to the pure basic form of an amine, as opposed to its salt form. The amine is usually a natural alkaloid product.

Cocaine can produce intense vasoconstrictive effects by directly stimulating the central nervous system and increasing peripheral catecholamines. The vasospastic action of cocaine is greatest at one hour after use and can be associated with ischemia, infarction and hemorrhagic injuries of most organ systems including the skin.16–18 The ischemic effects of cocaine in the skin can lead to acute multifocal skin necrosis,19 chronic skin ulcers,20 cutaneous fibrosis,21 blackened hyperkeratotic “crack hands”22 and claw-like “parrot beak” curvature of the nails. These changes are commonly found in association with pernio and some atrophy of the distal portions of the digital pulp secondary to ischemia. At skin-popping sites, there may be central pallor surrounded by ecchymosis due to the vasoconstrictive properties of cocaine acting locally at the injection site with hemorrhage occurring in the surrounding tissue. Skin popping is a method of drug administration whereby a substance is injected subcutaneously or intradermally, but not intravenously and not typically intramuscularly. Individuals with vasomotor instability are more susceptible to these types of reactions.23

Inadvertent or deliberate direct intraarterial injection of cocaine can cause severe tissue ischemia and necrosis via direct vasoconstriction. Individuals experience an initial intense burning pain, followed by cyanosis and marked edema. Compartment syndrome may also result. In the most severe cases necrosis leads to amputation.24,25 Skin popping also puts one at risk for developing secondary amyloidosis.

Cocaine-induced vasospasm may cause major internal organ injury including acute myocardial ischemia, cerebrovascular accidents, renal infarction26 and splenic infarction.18,27 Vasoconstriction of mesenteric vessels and the direct toxic effect of cocaine on gastrointestinal mucosa can result in acute abdominal crises (known as crack belly) secondary to perforations, intestinal ischemia and infarction.28,29

Various vasculitic and vasculopathic processes have been associated with cocaine use including pseudovasculitis,30 urticarial vasculitis,31 Churg–Strauss vasculitis,32 Raynaud phenomenon,33,34 Henoch–Schonlein purpura, necrotizing vasculitis35,36 and Buerger disease (see Chapters 163, 164, and 173).37,38

The local anesthetic properties of cocaine make it difficult for individuals to feel traumatic injury. This leaves users prone to repetitive trauma from the irritant properties of the drug itself and implements of drug delivery, thus exposing them to an increased risk of infection.39 Missing a vein and injecting into the surrounding tissue creates a niche environment in which bacteria can thrive.40 Repeated needlesticks increase the likelihood of cutaneous infection and transmission of blood-borne viruses.41

Mucosal manifestations of ischemia secondary to cocaine inhalation or smoking include dental caries,42 gingival recession,43 oral blisters44 and nasal and palatal perforation.45 Insufflating (snorting) cocaine may lead to recurrent epistaxis, intranasal crusting, rhinitis and chronic sinusitis.42,46 Inhalation utensils themselves can act as vectors for viruses and may induce “snorter's warts.” Nasal septum perforation reduces nasal support and results in a broad, flat nose or “saddle nose deformity.”46–49 Nasal septum perforation typically occurs prior to development of palatal perforation. Cocaine burns of the upper airway are associated with hoarseness, dysphonia, odynophagia, dysphagia and stridor.23,26,50–53 Crack cocaine smoke has a direct toxic effect on the corneal epithelium of the eye. Repeated exposure to the alkaloid smoke may cause an irritant effect leading to excessive eye rubbing and subsequent infectious complications, and chemical burns.51

Drug reactions including acute generalized exanthematous pustulosis54 and Stevens–Johnson syndrome 55 have also been reported.

The stimulant properties of cocaine are associated with increased metabolism and dramatic weight loss.56 Psychiatric conditions, most commonly delusions of parasitosis and subsequent formication are experienced approximately 20% of the time in cocaine users (also known as coke bugs)57 (see Chapter 104). Recent reports have emerged of febrile agranulocytosis and often vasculitis with prominent involvement of the ear lobes secondary to cocaine adulterated with levamisole, an anthelmintic medication used in veterinary medicine to control parasites in livestock.58,59

Heroin

Natural and semisynthetic derivatives of the opium poppy are known as opiates. Biologically natural opiates include morphine and codeine, while semisynthetic opiates such as heroin and hydromorphone are derived from biologically active opiates. Diacetylmorphine, or heroin, crosses the blood–brain barrier and binds opioid receptors in the brain, resulting in its euphoric, analgesic and anxiolytic effects. Heroin is the most common parenterally injected illicit drug, either by intravenous or subcutaneous (skin popping) administration. Heroin may also be inhaled. With a peak “rush” at 7–8 seconds, it is the fastest-acting and via smoking most potent opiate, accounting for up to 90% of opiate use in the United States.

Scarring is the primary cutaneous stigma of injection drug use. The antecubital fossa is the usual starting point of intravenous drug use, followed sequentially by the upper arms, hands, neck, feet, legs, groin and digits.60 Linear cord-like scars along a vascular distribution (track-marks), are formed after repeated injections along a superficial vein, resulting in venous thrombosis and subsequent fibrosis.61 (Fig. 105-3) Skin popping scars are irregular round hypopigmented or hyperpigmented, atrophic or hypertrophic scars or keloids.62 (see Fig. 105-2) Soot tattoos or shooting tattoos result from soot deposition or the introduction of foreign materials in the dermis after “cooking” of the drug and/or flaming of needles (Fig. 105-4).63

Diluting or “cutting” heroin to retail “street strength” is a common practice. Common diluents for white powder heroin include quinine, lactose, lidocaine, caffeine, lemon juice, inositol, dextrose, sucrose, procaine, starch, magnesium silicate and mannitol.64 Diluents may cause lymphatic destruction, foreign body granulomas, cutaneous nodules, ulcerations, panniculitis and dermal sclerosis secondary to irritation and dermal inflammatory processes (Fig. 105-5).65–67 The subsequent vascularized granulation tissue in and around chronic ulcers may be used as a site for drug injection.20 (see eFig. 105-5.1) Black tar heroin is a dark, gummy form of heroin that is less refined and cheaper than the white powder variant. It is mixed with a variety of diluents including dextrose, burnt cornstarch, instant coffee and dirt.68 The mixture may also contain dust and pathogens introduced during the process of manufacturing or storage.64,66 Irritant substances can also cause sterile chemical cellulites and abscesses.

Cutaneous infections are common in injection drug users (Table 105-1). Skin popping and black tar heroin use are associated with cutaneous necrosis and necrotizing ulcers.69–72 An increase in Clostridial infections including wound botulism due to Clostridium botulinum, tetanus due to Clostridium tetani, and rapidly progressive myonecrosis with a fulminant shock syndrome due to Clostridium sordellii have been observed with the use of black tar heroin in California.73–76

Fungi have been cultured from confiscated heroin specimens.77 Systemic candidosis characterized by painful nodules and pustules on the scalp and hair-bearing areas, chorioretinitis or uveitis, and costochondritis has been described in individuals injecting brown heroin diluted with lemon juice.78

Inhaling smoke and then exhaling it into another individual's mouth (known as shotgunning) is associated with efficient transmission of respiratory pathogens. 79

Opiates induce histamine release that results in subsequent pruritus that starts almost immediately after heroin injection and can last 10 minutes to 24 hours.80 Urticaria, severe angioedema and bronchospasm have also been reported with heroin use.80

Rare morbilliform eruptions, fixed drug eruptions and a case of toxic epidermal necrolysis have also been reported.62,64,81 Adulterants are thought to be responsible for most of these reactions.

Secondary systemic amyloidosis is an important cause of renal disease in heroin users. Its pathogenesis is thought to be associated with chronic antigenic stimulation and prolonged inflammation secondary to cutaneous infections. Patients were observed to progress to end stage renal disease over several months to 3 years.82

3,4-Methylenedioxymethamphetamine

3,4-methylenedioxymethamphetamine (MDMA, ecstasy), along with lysergic acid diethylamide (LSD) and hallucinogenic mushrooms, is one of the most commonly used illicit hallucinogens (Table 105-1). More than 7 million persons have tried MDMA at least once in their lifetime. MDMA is a synthetic stimulant with psychoactive properties that acts both by causing a massive synaptic release of serotonin, and to a lesser extent dopamine and norepinephrine, as well as inhibiting the reuptake transporters within the synapse. Its short-term effects include inducing euphoria, a sense of enhanced intimacy with others, and diminished anxiety and depression. Adverse health effects can include nausea, chills, sweating, teeth clenching, muscle cramping, and blurred vision. MDMA is usually ingested, but may be injected or inhaled with effects lasting for 3–6 hours. It is frequently used in combination with alcohol, cannabis, amphetamine or cocaine, resulting in unpredictable effects.83

MDMA is associated with xerostomia and is therefore often coupled with soft drinks, which may lead to dental caries. The neurotransmitter release associated with MDMA induces bruxism, trismus and teeth grinding that can wear down tooth enamel. Direct application of MDMA to the gums may cause necrotizing gingivitis and widespread perioral and intraoral swelling. MDMA can also interfere with systemic temperature regulation that can, rarely, be lethal.

Methamphetamine

Methamphetamine is a very addictive synthetic stimulant that affects the brain and central nervous system through the release of dopamine, norepinephrine, and serotonin. By concurrently blocking reuptake of these neurotransmitters, sensations of euphoria, lowered inhibitions, feelings of invincibility, and hyperactivity are produced.84 Metamphetamine a white, odorless, bitter-tasting powder that can be ingested orally, snorted or injected. It may also be smoked in its rock “crystal” form.85 Short-term effects include feelings of euphoria, decreased fatigue associated with difficult life situations, headache, difficulty concentrating, diminished appetite, abdominal pain, vomiting, diarrhea, disordered sleep, paranoid or aggressive behavior, and psychosis. Long-term use of methamphetamine use is associated with anorexia, neurotoxicity, neurodegeneration, and clinical depression that may lead to homicidal and suicidal ideation and action.85

An increased rate of skin and soft tissue infections have been reported in methamphetamine users, including increased rates of methicillin-resistant Staphylococcus aureus (MRSA) infections in noninjection drug users. Methamphetamine use is associated with formication that can lead to subsequent skin picking, skin breakdown, and portals of infection (see eFig. 105-5.2). Use of methamphetamine and other sexually stimulating drugs can also increase direct skin-to-skin sexual contact and transmission of MRSA86 (Table 105-1).

Methamphetamine users are at risk for developing meth mouth, or oral decay characterized by poor oral hygiene, xerostomia and rampant caries typically on the smooth surfaces of teeth, and excessive tooth wear.87 Methamphetamine use has also been associated with psychosis and subsequent self-injurious behavior including genital mutilation.88

Sedatives

Sedatives as a class of drugs includes benzodiazepines, hydroxybutyrate, flunitrazepam and cannabis. Cutaneous manifestations and reactions to this group of drugs is quite rare, however drug reactions have been rarely associated with benzodiazepines, including type IV morbilliform drug hypersensitivity eruptions,89 acute generalized exanthematous pustulosis to tetrazepam90 and erythema multiforme to clonazepam.91

Anabolic Steroids

Most anabolic steroids are synthetic substances similar to the male sex hormone testosterone. They may be ingested or injected, and are used especially by athletes to build muscle and enhance athletic performance. In 2000, approximately 3.6% of male and 0.9% of female twelfth graders in the United States had used anabolic steroids. Their abuse is most commonly associated with acne vulgaris, striae formation and alterations in hair growth.

Anabolic steroids induce sebaceous gland enlargement and the development of comedones through abnormal follicular keratinization.92,93 Steroid-associated acne is characteristically distributed on the face, shoulders, chest and back.93 It can progress to acne conglobata and fulminans secondary to the brisk immune response to Propionibacterium acnes in individuals who have never even had acne.94 Steroid-associated acne does not always respond to routine therapy and may persist for weeks to months following discontinuation of the drugs (see Chapter 80).93,95

Anabolic steroid use is also associated with alterations in hair growth, including hirsutism and androgenic alopecia, both of which are often more noticeable in women and may not be reversible with discontinuation of the drug.93,96,97 Males can develop testicular atrophy, gynecomastia and infertility. Women may experience menstrual changes, male-pattern alopecia, and deepening of the voice. Teenagers risk permanently stunted height and accelerated pubertal changes.

Steroid use is associated with striae formation secondary to dramatic hypertrophy of muscle tissue.98 Gingival enlargement has also been observed in those using anabolic steroids for greater than one year. Systemic effects of steroid abuse include hepatic damage, jaundice, hypertension and dyslipidemia.

Bacterial abscesses may occur at steroid injection sites secondary to nonsterile injection techniques.93,96 Repeated injection into the same site can result in inflammation and oil-induced granuloma formation.99 Soft tissue pseudotumors100 and rhabdomyolysis101 have also been reported in injectors.

In addition to causing de novo conditions, anabolic steroid use is also associated with exacerbation of existing acne and psoriasis.93 Case reports have described exacerbation of angiolipomas102 and latent acute hereditary coproporphyria as well.103

Tobacco

Through the use of tobacco, nicotine is one of the most heavily used addictive drugs in the United States. Cigarette smoking accounts for 90% of lung cancer cases in the US. Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana, which can be smoked or chewed (more precisely, placed between gingival and buccal mucosa) to allow nicotine absorption via oral mucosa. Nicotine in the tobacco leaves is responsible for the vasoconstrictive effects of smoking via increased vasopressin secretion and stimulation of the sympathetic nervous system, thereby causing peripheral vasoconstriction.104–108 Smoking a single cigarette can produce cutaneous vasoconstriction for up to 90 minutes.109 Smoking decreases tissue oxygenation via vasoconstriction and by increasing carboxyhemoglobin, thereby limiting the blood's oxygen carrying capacity.110 Smoking also increases platelet aggregation111 and blood viscosity,112 and decreases prostacyclin formation.113 This combination of mechanisms also leads to impaired postoperative wound healing in smokers.114,115 The tar in cigarettes increases a smoker's risk of lung cancer, emphysema, and bronchial disorders. The carbon monoxide in smoke increases the chance of cardiovascular diseases.

Although the mechanism is unknown, smoking tobacco has also been linked with premature aging and rhytid formation. Elastin from photoprotecting skin in smokers is thick and fragmented, resembling that of sun-damaged skin but involving the reticular rather than the papillary dermis. Chronic dermal ischemia of as well as the decreased collagen synthesis likely play roles in the damaging elastic fibers.116 Increased plasma neutrophil elastase activity secondary to smoking may contribute to abnormal elastin.117 Smoking also causes a yellow–brown discoloration of the fingers and fingernails of digits habitually holding the cigarette (Fig. 105-6).118

Cigarette smoking and chewing tobacco use are associated with a number of mucosal conditions. Leukokeratosis nicotinica palati (nicotine stomatitis, smoker's palate) is characterized by uniform keratosis of the hard palate with multiple tiny umbilicated erythematous papules representing the inflamed orifices of minor salivary glands.119 This benign oral lesion is seen exclusively in smokers and is caused by the tars and heat in tobacco smoke. Resolution is usually complete within 2 weeks of smoking cessation. All forms of tobacco use play a significant causative role in the development of leukoplakia.120 Leukokeratosis nicotinica glossae (also known as tongue) is a homogeneous leukoplakia affecting the anterior two-thirds of the dorsal tongue.121 Acute necrotizing ulcerative gingivitis “trench mouth,” Vincent disease is caused by bacteria but is not communicable. Smokers tend to have fewer oral aphthous ulcers than nonsmokers due to decreased mucosal blood flow resulting from the vasoconstrictive effect of nicotine. Yellow discoloration of teeth secondary to tar deposition is also commonly observed.

Oral verrucous carcinoma, black hairy tongue, oral melanosis and oral warty dyskeratoma have been linked to tobacco use, but the connection is not as strong as in the aforementioned conditions.122,123

All forms of tobacco are associated with an increased risk of oral cancer.124–127 Cigarette smoke may act as a direct carcinogen or via systemic absorption.128,129 Smokers are also at an increased risk of developing squamous cell carcinomas at sites other than the oral mucosa, likely because of the immunosuppressive effects of smoking.130–132 Immune dysregulation associated with smoking is thought to be the reason that smokers with melanomas present with more advanced lesions and have a poorer disease prognosis.133,134

Thromboangiitis obliterans (Buerger disease) is an obstructive vascular disease that is indisputably associated with heavy cigarette smoking in young men. Cutaneous manifestations include blanching, cyanosis, burning, tingling, ulceration, necrosis, and gangrene (see Chapter 170).

Cigarette smoking has been shown to exacerbate and possibly induce palmoplantar pustulosis.135,136

Both allergic and irritant contact dermatitis characterized by itching and burning, have been documented to nicotine patches.137 Allergic contact dermatitis to the tobacco leaf has also been reported in tobacco harvesters and factory workers.138,139

Betel

Betel (Piper betle) belongs to the Piperaceae family; its leaf has an important social and cultural role in South Asia, Southeast Asia and the South Pacific. Betel leaves are chewed with the areca nut (also known as betel nut), calcium hydroxide, Acacia catechu bark, and occasionally tobacco in a wrapped package known as “betel quid.” Betel leaves are used as a stimulant, antiseptic and breath freshener. The areca nut contains the alkaloid and stimulant arecoline which promotes salivation and stains saliva and teeth dark red to rust-colored. Calcium hydroxide keeps the active ingredients alkaline, thereby enabling its sublingual absorption and entry into the bloodstream.

Continuous chewing of betel quid maintains constant moisture at the oral commissures which, when coupled with continuous friction of opposing surfaces, causes maceration, erosion and fissures. These lesions can be mistaken for angular cheilitis, candidiasis or vitamin-deficiency associated perleche.140 The mixture is usually kept between the teeth and lip and may thus cause burning and erosions of the buccal mucosa.140 Chewer's mucosa results from the direct chemical action of the quid and/or traumatic effect of chewing, and is characterized by a brownish–red discoloration of the buccal mucosa with an irregular desquamative epithelial surface. These mucous membrane findings are not thought to be malignant or premalignant.141 Oral lichenoid lesions regress with decrease in frequency, duration or change in site of placement of the quid.142

Oral submucous fibrosis is directly related to betel quid chewing and affects the buccal mucosa, lips, retromolar areas, soft palate and occasionally the pharynx and esophagus.143 It is characterized by prodromal oral dysesthesia aggravated by spicy foods, followed by early blanching mottled mucosal lesions and subsequent late development of palpable vertical fibrous bands in the buccal mucosa and around the mouth opening requiring surgical release for sufficient opening of the mouth.144 Trismus, dysphagia, xerostomia, rhinolalia and tongue stiffening present late in the disease course. Mucosal petechiae, leukoplakia and epithelial dysplasia are also seen.145,146 The most serious complication of oral submucous fibrosis is the development of oral carcinoma, which can be seen in up to 10% of users and is typically localized to the buccal tongue and labial mucosa.147 Of all oral cancers in Taiwan, as many as 86.2% of cases have been reported to be in betel quid chewers.148

Polysubstance Abuse

Polysubstance abuse, the concurrent use of several drugs with different pharmacologic effects, is becoming increasingly common. The diversity of reported drug use combinations suggests that achieving some perceptible change in state may be the primary motivator driving this practice. One drug may be used to enhance the effects of another, as with the combined use of benzodiazepines and methadone or cocaine and heroin (speedballs). Polysubstance abuse can cause adverse health consequences, such as pulmonary disease, reproductive dysfunction and immunosuppression in chronic cocaine and psychostimulant abuse. It may also exacerbate preexisting conditions such as hypertension and cardiac disease. The concurrent use of some drugs, including cocaine and opiates, is frequently associated with deleterious behavior such as needle sharing by injection drug users.

In addition to the local reactions and systemic effects of specific drugs themselves complications of drug use must also be considered.

Injection drug use is associated with inoculation and transmission of infectious agents leading to local skin and soft tissue infections and abscesses, as well as the subsequent hematogenous spread of microbes. Gram-positive cocci including Staphylococcus aureus, group A β-hemolytic streptococcus and other streptococci are the most commonly observed microbial agents.149–151 Anaerobes are the second most common group of bacteria to be isolated, while Gram-negative bacteria are less commonly isolated. The source of the pathogens is variable, but most originate from the flora of the skin and oropharynx secondary to needle-licking practices and use of saliva to clean or moisten skin and injection implements.149 Abscesses and cellulitis occur in 22%–65% of drug users152 (Fig. 105-7). Irritant substances including the drug or its diluents may cause sterile chemical cellulitis and abscesses. Systemic infections including bacteremia, endocarditis, osteoarthritis, and systemic candidosis may result. Systemic candidosis is the most common systemic fungal infection in injection drug users (Table 105-2).

Direct intra-arterial injection of drugs may cause severe ischemia and necrosis. Early intense burning is noted in the injected area, followed by marked edema, compartment syndrome, cyanosis, and livedoid patches of the affected limb within a few hours. Distal necrosis may occur in the most severe cases, and has been seen with the use of drugs such as cocaine, heroin, pentazocine, diazepam, amphetamine and others25,153,154 The local cytotoxicity of a drug may cause a chemical endarteritis resulting in vasospasm and thrombosis.

The behavioral effects of injection drug use has been associated with an increased risk of sexually transmitted diseases as well as blood-borne diseases transmitted through unsterilized needles including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV) (Table 105-2).

The repeated trauma of venipuncture, local infections and the irritant drugs and adulterants can lead to superficial and deep venous thrombosis. Chronic venous insufficiency can result from vein trauma, necrotic ulcers at sites of past subcutaneous injection, vein thrombosis and blockage of the lymphatic system.155,156

Other noninfectious diseases associated with drug use include psychiatric disease, accidental injury due to altered mental status and trauma due to criminal violence or domestic abuse.

While mucocutaneous findings can be suggestive of drug use drug testing is needed to identify the agents used. Bodily fluids including saliva, blood, urine and hair can be used in drug detection. Urinalysis for qualitative detection of psychoactive substances and their metabolites is often the fastest way to determine ingestion of a substance (Table 105-3).

Systemic conditions secondary to the effects of substance abuse should also be part of the evaluation of these patients. Cutaneous infections at sites of trauma, ulcers, or necrosis should be swabbed or biopsied for culture to identify and treat causative organisms. Thorough evaluation and imaging may be required to rule out injury to or involvement of vital organs and bony structures. In injection drug users, thorough cardiac evaluation and examination of mucocutaneous and acral surfaces should be undertaken to access for embolic phenomenon. Evaluation for transmitted infections such as HIV, hepatitis and sexually transmitted diseases may be required.

It is imperative to rule out primary infectious causes of ulcers, nodules, skin and subcutaneous infections in suspected drug users. Inflammatory and vasculopathic processes such as pyoderma gangrenosum, livedoid vasculopathy and medium vessel vasculitides must be considered in the setting of ulcers and nodules. Evidence of distal vascular compromise can be seen in pernio, thromboembolic phenomenon and Raynaud phenomenon. The edematous phase of scleroderma, eosinophilic fasciitis and secondary lymphatic obstruction are rare entities to consider the setting of distal extremity swelling. Infectious and noninfectious granulomatous diseases [including tuberculosis, leishmaniasis, granulomatosis with polyangiitis (Wegener's) and sarcoidosis] can present with nasopalatal infiltration and perforation. Patients with pruritus and formication may require evaluation for infestation, metabolic or psychiatric etiologies of their symptoms.

A detailed discussion of the treatment of drug abuse and dependence is beyond the scope of this chapter, but it is essential to recognize that these are chronic illnesses that require long-term strategies. Combined medical and behavioral therapy are important elements of a therapeutic process comprising detoxification, treatment and relapse prevention. Amelioration of withdrawal symptoms is key to initiation of therapy. A multidisciplinary approach including addiction counseling, social work support and management of associated infectious, vascular, cardiac and hepatic complications is critical to comprehensive care.

Potential therapies for opiate dependence include drug detoxification (office-based, inpatient or ultra rapid under anesthesia), agonist maintenance (injectable diacetylmorphine, methadone, levomethadyl or buprenorphine), antagonist maintenance (naltrexone)and pharmacologic treatment of withdrawal symptoms (clonidine, lofexidine or guanfacine).

Treatment options for tobacco addiction include nicotine replacement therapies (patch, spray, gum and lozenges). Bupropion and varenicline have been approved by the Food and Drug Administration for management of nicotine addiction. Behavioral interventions include group and individual therapies, and telephone quitlines.

Outpatient and residential treatment centers can provide environments in which individuals can participate in therapeutic communities and benefit from behavioral therapy and peer support. Alternative therapies including acupuncture may also prove useful in combination with medical and behavioral therapeutic interventions. Although relapses are common, successful outcomes are accomplishable, indicating the importance of candid, supportive, nonjudgmental, care-facilitating discussions in patients whose drug use has been revealed through skin examination.

The transmission of infectious disease via injection drug use can be addressed by encouraging physicians to prescribe sterile injection equipment, setting up injection rooms staffed by healthcare personnel who can provide advice on safe injection techniques and instituting strictly supervised heroin, diamorphine or buprenorphine prescription programs for long-term injectors.157 This may help reduce the risk of life-threatening infection from nonsterilized drugs, prevent overdose from drugs of unknown purity, break the link between drug use and criminal activity to acquire drugs and decrease the number of injections in public places.